The effect of volatile anesthetics and barbiturates on the margin of safety of neuromuscular transmission will be measured in vitro in isolated guinea pig lumbrical muscles. The magnitude and kinetics of phase II neuromuscular block produced by drugs like succinylcholine will be examined quantitatively in isolated mammalian muscles by comparing interference with neuromuscular transmission as indicated by the indirect twitch response directly with electrical changes at the end-plate region recorded by the moving fluid electrode technique. The drug-receptor dissociation constant will be determined for selected new neuromuscular blocking agents of the type exemplified by AH8165. Statistical procedures for analysis of concentration-time curves will be further developed, in particular to handle the problem of a multiphasic exponential washout. The effect of anesthetics and barbiturates on drug induced membrane electrical noise in isolated mammalian muscles will be determined. Experiments will be done to pin-point the site of the vagolytic action of pancuronium, in particular to distinguish an action on endings of the vagus from one on the ganglia.